Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expressions and pathway activation

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• 作者：Ken Onitsuka ; Tomomi Ide ; Shinobu Arai ; Yuko Hata ; Yoshinori Murayama ; Kazuya Hosokawa ; Takafumi Sakamoto ; Tomoyuki Tobushi ; Kazuo Sakamoto ; Takeo Fujino ; Kenji Sunagawa
• 关键词：Cardiac phase ; Isolated heart ; Mechanical load ; Microarray ; Myocardial adaptation
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：64
• 期：Complete
• 页码：30-38
• 全文大小：897 K

文摘

The heart has remarkable capacity to adapt to mechanical load and to dramatically change its phenotype. The mechanism underlying such diverse phenotypic adaptations remains unknown. Since systolic overload induces wall thickening, while diastolic overload induces chamber enlargement, we hypothesized that cardiac phase-sensitive mechanisms govern the adaptation. We inserted a balloon into the left ventricle (LV) of a Langendorff perfused rat heart, and controlled LV volume (LVV) using a high performance servo-pump. We created isolated phasic systolic overload (SO) by isovolumic contraction (peak LV pressure > 170 mmHg) at unstressed diastolic LVV [end-diastolic pressure (EDP) = 0 mmHg]. We also created pure phasic diastolic overload (DO) by increasing diastolic LVV until EDP > 40 mmHg and unloading completely in systole. After 3 hours under each condition, the myocardium was analyzed using DNA microarray. Gene expressions under SO and DO conditions were compared against unloaded control condition using gene ontology and pathway analysis (n = 4 each). SO upregulated proliferation-related genes, whereas DO upregulated fibrosis-related genes (P < 10^? 5). Both SO and DO upregulated genes related functionally to cardiac hypertrophy, although the gene profiles were totally different. Upstream regulators confirmed by Western blot indicated that SO activated extracellular signal-regulated kinase 1/2, c-Jun NH₂-terminal kinase, and Ca^2 +/calmodulin-dependent protein kinase II (3.2-, 2.0-, and 4.7-fold versus control, P < 0.05, n = 5), whereas DO activated p38 (2.9-fold, P < 0.01), which was consistent with the downstream gene expressions. In conclusion, pure isolated systolic and diastolic overload permits elucidation of cardiac phase-sensitive gene regulation. The genomic responses indicate that mechanisms governing the cardiac phase-sensitive adaptations are different.